ABSTRACT The proposed study: Identifying the molecular systems, networks, and key molecules that underlie cognitive resilience is in response to RFA-AG-17-061. The overall goal of the proposed study is to identify the molecular networks underlying resilience to AD, other age-associated neuropathologies and risk factors associated with resilience. The proposal is highly responsive to the RFA in that it is focused on the function of networks supporting cognitive resilience. Specifically, we will generate high-dimensional molecular data, to which we will apply systems biology approaches, and then integrate these with measures of resilience that rely on longitudinal cognitive data and assays of age-related neuropathologies. A key outcome of this research will be linking environmental, lifestyle and experiential factors to specific molecular networks. In addition to protein validation in humans, we will utilize living human brain networks as a validation ?model system?. We are able to do this, b ecause for the first time our omics will be acquired from persons who previously provided fMRI data. Therefore, we can provide a unified perspective on the basis of resilient brain function in molecular and brain networks, which provides high confidence validated molecules and networks driving resilience to AD and age-related neuropathologies in humans. Our main resources for the proposed study are two longitudinal studies of aging, which provide neuroimaging, omic detailed neuropathology, longitudinal cognition scores and a quantitative measure of resilience for each person. From these cohorts, in Aim 1 we will acquire RNAseq and TMT proteomics (9000+ measured proteins) from regions of the brain whose molecular structure varies in synchrony with a continuous measure of resilience, based on MRI of this cohort. After identifying the molecular systems active in these regions, we will (Aim 2) infer the networks contained within each molecular system, the connections between molecular systems, and the connections between molecular systems and resilience. Given the limitations of animal models in validating cognitive phenotypes, we utilize a unique resource to validate the gene and protein networks found to be associated with resilience. We will (Aim 3) use dynamic fMRI-based brain networks, previously acquired from the same individuals to validate the post-mortem molecular networks with this close proxy of cognitive function. Thus the proposal brings to bear several major perspectives on resilience ? longitudinal cognition, neuropathology, multiple omics and neuroimaging to identify novel networks and targets to stimulate resilience, producing a strong and sustained impact on the field.